The 'death receptor' subfamily of TNF receptors is known to mediated programmed cell death through recruitment of caspases to a death domainin the intracellular tail of the receptor. In the immune system, signaling through death receptors eliminates autoreactive T and B cells at a number of critical checkpoints in peripheral differentiation. Although elimination of the death receptor Fas/CD95 results in autoimmunity through blocking elimination of autoreactive T cand B cells, recent experimental evidence suggests that the adapter protein FADD and the initiator caspase-8 enzyme can also mediate some aspects of T cell activation. To study the cell-type specific function of death receptor signaling, we have generated transgenic mice overexpressing v-FLIP, a potent viral blocker of death receptor signal transduction. In T-cell specific CD2-vFLIP transgenic mice, decreased Fas-mediated apoptosis was seen, but more prominently, a defect in post-activation T cell survival was seen in vitro and in vivo, resulting in a severe deficit of memory phenotype peripheral CD8 T cells. In vitro experiments have suggested that the cellular defect resembles that of cytokine unresponsiveness, and detailed studies of IL-2 and IL-15 signaling in these transgenic mice are underway in collaboration with members of Dr. O'shea's group. Genetic crosses to test the role of IL-15 and Stat-5 in this phenomenon are underway with Dr. Tagaya's and Dr. Leonard's groups, respectively. Testing of the competency of v-FLIP expressing CD8 T cells to mature into effector and memory cells in response to an infectious challenge (Influenza PR8 strain) will be studied, as well as the competency of v-FLIP transgenic T cells in CD4-mediated (EAU, Dr. Caspi) and CD8-mediated Diabetes (RIP-Ova recipients of OT-1 Ova-specific T cells, Drs. Picirrilo and Shevach) are being studied. The long-term goals of this study are to better understand the cross-talk between apoptosis and survival signaling pathways in various lymphocyte subsets, and study the effexts of blocking apoptosis signaling at various levels on autoimmune disease models.